RESUMO
Zika virus (ZIKV) is a member of the Flaviviridae family that can cause neurological disorders and congenital malformations. The NS2B-NS3 viral serine protease is an attractive target for the development of new antiviral agents against ZIKV. We report here a SAR study on a series of substrate-like linear tripeptides that inhibit in a non-covalent manner the NS2B-NS3 protease. Optimization of the residues at positions P1, P2, P3 and of the N-terminal and C-terminal portions of the tripeptide allowed the identification of inhibitors with sub-micromolar potency with phenylglycine as arginine-mimicking group and benzylamide as C-terminal fragment. Further SAR exploration and application of these structural changes to a series of peptides having a 4-substituted phenylglycine residue at the P1 position led to potent compounds showing double digit nanomolar inhibition of the Zika protease (IC50 = 30 nM) with high selectivity against trypsin-like proteases and the proteases of other flavivirus, such as Dengue 2 virus (DEN2V) and West Nile virus (WNV).
Assuntos
Antivirais/farmacologia , Peptídeos/farmacologia , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Zika virus/efeitos dos fármacos , Antivirais/síntese química , Antivirais/química , Vírus da Dengue/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Peptídeos/síntese química , Peptídeos/química , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , RNA Helicases/antagonistas & inibidores , RNA Helicases/metabolismo , Serina Endopeptidases/metabolismo , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismo , Vírus do Nilo Ocidental/efeitos dos fármacos , Zika virus/enzimologiaRESUMO
Tourette syndrome (TS) and attention-deficit and hyperactivity disorder (ADHD) are co-morbid neurodevelopmental conditions affecting more commonly male patients. We set out to determine the impact of co-morbid ADHD on cognitive function in male children with TS by conducting a controlled study. Participants included four matched groups of unmedicated children (age range 6-15 years): TS (n=13), TS+ADHD (n=8), ADHD (n=39), healthy controls (n=66). Following clinical assessment, each participant completed a battery of tests from the Wechsler Intelligence Scale for Children-III, the Italian Battery for ADHD, the Tower of London test, the Corsi test, and the Digit Span test. All patient groups reported significantly lower scores than healthy controls across the neuropsychological tests involving executive functions. The TS+ADHD group was the most severely affected, followed by the ADHD group and the TS group, particularly in the tests assessing planning ability, inhibitory function, working memory and visual attention, but not auditory attention. Problems in executive functions are more common in patients with neurodevelopmental disorders than controls. Deficits in planning ability, inhibitory function, working memory and visual attention reported by children with TS appear to be more strongly related to the presence of co-morbid ADHD symptoms than core TS symptoms.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Cognição , Testes Neuropsicológicos , Síndrome de Tourette/epidemiologia , Síndrome de Tourette/psicologia , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Criança , Cognição/fisiologia , Comorbidade , Função Executiva/fisiologia , Feminino , Humanos , Testes de Inteligência/normas , Masculino , Memória de Curto Prazo/fisiologia , Testes Neuropsicológicos/normas , Síndrome de Tourette/diagnósticoRESUMO
Histamine H(1) and serotonin 5-HT(2A) receptors mediate two different mechanisms involved in sleep regulation: H(1) antagonists are sleep inducers, while 5-HT(2A) antagonists are sleep maintainers. Starting from 9'a, a novel spirotetracyclic compound endowed with good H(1)/5-HT(2A) potency but poor selectivity, very high Cli, and a poor P450 profile, a specific optimization strategy was set up. In particular, we investigated the possibility of introducing appropriate amino acid moieties to optimize the developability profile of the series. Following this zwitterionic approach, we were able to identify several advanced leads (51, 65, and 73) with potent dual H(1)/5-HT(2A) activity and appropriate developability profiles. These compounds exhibited efficacy as hypnotic agents in a rat telemetric sleep model with minimal effective doses in the range 3-10 mg/kg po.
Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Antagonistas dos Receptores Histamínicos H1/síntese química , Hipnóticos e Sedativos/síntese química , Receptor 5-HT2A de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/síntese química , Sono/efeitos dos fármacos , Compostos de Espiro/síntese química , Animais , Disponibilidade Biológica , Encéfalo/metabolismo , Linhagem Celular , Córtex Cerebral/metabolismo , Cricetinae , Cricetulus , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Antagonistas dos Receptores Histamínicos H1/química , Antagonistas dos Receptores Histamínicos H1/farmacologia , Humanos , Hipnóticos e Sedativos/química , Hipnóticos e Sedativos/farmacologia , Masculino , Microssomos Hepáticos/metabolismo , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Antagonistas do Receptor 5-HT2 de Serotonina/química , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Transtornos do Sono-Vigília/tratamento farmacológico , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A novel imidazobenzazepine template (5a) with potent dual H(1)/5-HT(2A) antagonist activity was identified. Application of a zwitterionic approach to this poorly selective and poorly developable starting point successfully delivered a class of high quality leads, 3-[4-(3-R(1)-2-R-5H-imidazo[1,2-b][2]benzazepin-11-yl)-1-piperazinyl]-2,2-dimethylpropanoic acids (e.g., 9, 19, 20, and 21), characterized by potent and balanced H(1)/5-HT(2A) receptor antagonist activities and good developability profiles.
Assuntos
Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/uso terapêutico , Transtornos do Sono-Vigília/tratamento farmacológico , HumanosAssuntos
Hidrazinas/química , Receptores de Grelina/antagonistas & inibidores , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Transtornos da Alimentação e da Ingestão de Alimentos/tratamento farmacológico , Humanos , Hidrazinas/síntese química , Hidrazinas/uso terapêutico , Receptores de Grelina/metabolismo , Relação Estrutura-AtividadeRESUMO
Data from the Psychoeducational Profile-Revised (PEP-R) were analysed in a sample of 46 children, aged from 1.7 to 5.11 years, of whom 21 had autistic disorder (AD) and 25 had pervasive developmental disorder not otherwise specified (PDD-NOS). Analysis with a t-test for independent samples revealed a significant difference (p < 0.05) between children with AD and those with PDD-NOS on both developmental and behavioural PEP-R scales, supporting the utility of the PEP-R in discriminating between two diagnostic groups. This study emphasizes the effectiveness of the PEP-R as a tool for the early assessment of children with pervasive developmental disorders.
Assuntos
Transtorno Autístico/diagnóstico , Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Testes Neuropsicológicos/estatística & dados numéricos , Transtorno Autístico/psicologia , Transtornos do Comportamento Infantil/diagnóstico , Transtornos do Comportamento Infantil/psicologia , Transtornos Globais do Desenvolvimento Infantil/psicologia , Pré-Escolar , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/psicologia , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Inteligência , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Transtornos do Desenvolvimento da Linguagem/psicologia , Masculino , Psicometria/estatística & dados numéricos , Valores de Referência , Reprodutibilidade dos TestesRESUMO
To identify new CRF(1) receptor antagonists, an attempt to modify the bis-heterocycle moiety present in the top region of the dihydropyrrole[2,3]pyridine template was made following new pharmacophoric hypothesis on the CRF(1) receptor antagonists binding pocket. In particular, the 2-thiazole ring, present in the previous series of compounds, was replaced by more hydrophilic non aromatic heterocycles able to make appropriate H-bond interactions with amino acid residues Thr192 and Tyr195. This exploration, followed by an accurate analysis of the substitution of the pendant aryl ring, enabled to identify in vitro potent compounds showing excellent pharmacokinetics and outstanding in vivo activity in animal models of anxiety, both in rodents and primates.
Assuntos
Piridinas/síntese química , Piridinas/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Feminino , Membro Anterior/efeitos dos fármacos , Gerbillinae , Humanos , Masculino , Modelos Químicos , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Testes Psicológicos , Piridinas/química , Pirróis/química , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Ultrassom , Vocalização Animal/efeitos dos fármacosAssuntos
Ansiedade/tratamento farmacológico , Depressão/tratamento farmacológico , Desenho de Fármacos , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Ansiedade/patologia , Hormônio Liberador da Corticotropina/metabolismo , Depressão/patologia , Modelos Químicos , Pirazóis/síntese química , Pirazóis/farmacocinética , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
Corticotropin-releasing factor (CRF), a 41 amino acid peptide neurohormone synthesised by specific hypothalamic nuclei in the brain, is implicated in stress-related function. Antagonism of CRF(1) receptors is an attractive therapeutic approach for the treatment of depression and anxiety. Unsaturated tetrahydrotriazaacenaphthylenes of general structure 3 have been identified as potent and selective CRF(1) receptor antagonists with a suitable oral pharmacokinetic profile.
Assuntos
Naftalenos/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Administração Oral , Humanos , Naftalenos/administração & dosagem , Naftalenos/química , Naftalenos/farmacocinética , Proteínas Recombinantes/antagonistas & inibidoresRESUMO
Two new classes of potent and selective CRF(1) receptor antagonists are presented. Exploration of general templates 3 and 4 through modifications of the top amine and bottom phenyl substituents led to optimization of the in vitro affinity and pharmacokinetic profiles. The typical alkyl chains present in the top region of CRF(1) antagonists were replaced by substituted heteroaryl moieties, leading to a dramatic improvement of the metabolic stability. This improvement was apparent when the compounds were dosed in vivo: several compounds exhibited low plasma clearance, good oral bioavailability, and high brain penetration. As a consequence of their outstanding pharmacokinetic profiles, these CRF(1) antagonists, as exemplified by compound 4 fi (4-(4-bromo-3-methyl-1H-pyrazol-1-yl)-7-(2,4-dichlorophenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine), produced a dose-dependent "anxiolytic-like" effect when administered orally, decreasing the vocalization of rat pups.
Assuntos
Pirimidinas/química , Pirimidinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Ansiolíticos/química , Ansiolíticos/farmacologia , Relação Dose-Resposta a Droga , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Pirimidinas/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Vocalização Animal/efeitos dos fármacosRESUMO
The synthesis of a series of carbazole derivatives and their SAR at the NPY Y1 receptor is described. Modulation of physicochemical properties by appropriate decoration led to the identification of a high-affinity NPY Y1 antagonist that shows high brain penetration and modest oral bioavailability.